August 17, 2012

Poxviruses Adapt Quickly To Fight Host Of Viral Defenses

Researchers recently discovered how poxviruses, viruses that contain DNA, can change quickly; in particular, they have an “accordion-like” way of viral adaption to fight against host viral defenses.

Poxviruses, which include smallpox, can lead to a number of diseases in both humans and animals. They are seen as harmful, as they can pass through the species barrier with low mutation rates. Recently, there has been renewed interest in smallpox as a tool for bioterrorism and for other poxviruses that can be passed from animals to humans.

Researchers hope to better understand the role of poxviruses to develop more effective antiviral methods. In particular, scientists at Fred Hutchinson Cancer Research Center collaborated with other institutions to determine how poxviruses change to adapt against their host defenses. The findings of the research were published in a recent edition of the journal Cell.

"Poxviruses encode a variety of genes that help them to counter host immune defenses and promote infection," explained Nels C. Elde, an assistant professor of human genetics at the University of Utah School of Medicine who worked on the project, in a prepared statement. "Despite ample evidence that the poxvirus genome can undergo adaptive changes to overcome evolving host defenses, we still don't know that much about the mechanisms involved in that adaptation."

The research, conducted by Harmit S. Malik of the Hutchinson Center´s Basic Sciences Division and Elde, highlighted how large, double-stranded DNA viruses could avoid host immunity and become drug resistant. To better understand the relationship between the viruses along with animals and humans, the researchers completed an experiment in cell culture that utilized vaccinia virus to evolve and adapt virally as it does in nature.

"Dramatically, serial propagation of this 'weaker' virus rapidly resulted in strains that became much more successful at replicating in human cells," noted Malik, who also serves as an Early Career Scientist of the Howard Hughes Medical Institute, in the statement.

The scientists observed that the virus was able to defeat protein kinase R, a previous obstacle to poxvirus infection, by choosing to temporarily increase the number of copies of the K3L gene in its genetic makeup.

"This highly specific and rapid gene amplification was unexpected," noted Elde in the statement. "Our studies show that increasing K3L copy number leads to increased expression of K3L and enhanced viral replication, providing an immediate evolutionary advantage for those viruses that can quickly expand their genome."

The rapid change of the virus is similar to the movement of a musical accordion and a virus that could adapt quickly had an evolutionary advantage over other viruses.

"As the K3L copy number increased in subsequent rounds of replication, so did expression of the K3L protein and subsequent inhibition of the immune response," remarked Malik in the statement.

The researchers also saw that, besides expanding a strain of the vaccinia, the virus contracted following the acquisition of an adaptive mutation.

"Our studies suggest that despite their transient nature, gene expansions may provide a potent means of adaptation in poxviruses, allowing them to survive either immune or pharmacological challenges," concluded Malik in the statement. "Recognizing the means by which they undergo this expansion may provide more effective antiviral strategies against these and related important pathogens."